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PubMed2006

Tumor-derived interleukin-4 reduces tumor clearance and deviates the cytokine and granzyme profile of tumor-induced CD8+ T cells.

An interleukin (IL)-4-containing tumor environment is reported to be beneficial for immune clearance of tumor cells in vivo; however, the effect of IL-4 on the effector CD8+ T cells contributing to tumor clearance is not well defined. We have used the immunogenic HLA-CW3-expressing P815 (P.CW3) mastocytoma and investigated whether IL-4 expression by the tumor affects tumor clearance and, if so, whether it alters the tumor-induced Vbeta10+ CD8+ T-cell response. P.CW3 were stably transfected with IL-4 or the empty control vector, and independent cell lines were injected i.p. into syngeneic DBA/2 mice. After apparent clearance of primary tumors over 12 to 15 days, secondary tumors arose that lacked surface expression and H-2-restricted antigen presentation of CW3 in part due to the loss of the HLA-CW3 expression cassette. Surprisingly, mice that received IL-4-producing tumor cells showed delayed primary tumor clearance and were significantly more prone to develop secondary tumors compared with mice receiving control tumor cells. Tumor clearance was dependent on CD8+ T cells. The IL-4-secreting P.CW3 tumor cells led to markedly higher mRNA expression of IL-4 and granzyme A and B but no differences in IFN-gamma and IL-2 production, cell proliferation, or ex vivo CTL activity in primary Vbeta10+ CD8+ T cells when compared with the control tumor cells. We concluded that tumor-derived IL-4 selectively changed the quality of the tumor-induced CD8+ T-cell response and resulted in unexpected negative effects on tumor clearance. These data bring into question the delivery of IL-4 to the tumor environment for improving tumor immunotherapy.

Animals↗
PubMed1986

Dietary fat and mammary cancer. II. Modulation of serum and tumor lipid composition and tumor prostaglandins by different dietary fats: association with tumor incidence patterns.

For investigation of the role of linoleic acid (LA) and its biologically significant metabolites in mammary tumor promotion by dietary fat, a detailed study of the fatty acid group composition of serum lipids, tumor neutral lipids, tumor phospholipids, and tumor prostaglandins (PG's) was conducted in female inbred F344 rats initiated with N-nitrosomethylurea (CAS: 684-93-5) and fed diets containing various types and amounts of fat. The oils, safflower [23%, high fat (HF); 5%, low fat], corn (23%, 5%), olive (23%, 5%), and coconut (23%) varied widely with respect to their LA content and their polyunsaturate:monounsaturate:saturate ratios (9:1:1, 4.6:2.6:1, 0.6:5.9:1, and 0.008:0.05:1, respectively, for safflower, corn, olive, and coconut oils). A modified hexane-based technique was used for extraction of serum and tumor lipids. Total tumor lipids ranged from a low of 5 to a high of 228 mg/g (wet wt) with no differences found among the 7 dietary groups. The phospholipid content of the tumors ranged from 27 to 47% of total tumor lipid, again with no differences seen among dietary groups. Total serum lipids varied from a low of 3.77 mg/ml (safflower oil, 23%) to a high of 6.11 mg/ml (coconut oil, 23%), and an overall inverse trend was observed between total serum lipids and tumor incidence for the 4 HF diet groups. Serum cholesterol levels were significantly depressed in the HF safflower oil and corn oil groups compared to those in all other dietary groups and, in general, varied inversely with respect to mammary tumor incidence. Serum and tumor neutral fatty acid profiles closely reflected those of the diet, while tumor phospholipids appeared more resistant to diet-induced changes. Olive oil-fed animals exhibited high levels of oleic acid in both serum and tumor lipids. The levels of the major metabolite of LA, arachidonic acid (AA), in tumor phospholipids were highly variable and did not equate with dietary or serum LA levels. A positive association was found among dietary LA, tumor PGE2, and mammary tumor incidence among the 4 HF groups; however, no association was found between tumor AA levels and either tumor PGE2 levels or mammary tumor incidence. The results of this study suggest that dietary LA may exert its effects on mammary tumor promotion by virtue of its role as a PG precursor; but the precise steps in this sequence and possible competitive interactions between essential fatty acids, monoenes, and saturates and the PG-synthesizing system remain to be determined.

Animals↗
PubMed1983

Tumor-associated macrophages of mouse mammary tumors. II. Differential distribution of macrophages from metastatic and nonmetastatic tumors.

Macrophage subpopulations were isolated by counterflow centrifugal elutriation from a number of closely related mammary tumors originally derived from a single spontaneous tumor in a BALB/cfC3H mouse. Each tumor line had its own distinct characteristics with regard to tumor cell distribution, macrophage size (density), macrophage content, and macrophage distribution. Although there is no correlation with the metastatic potential of the tumors for the first three characteristics listed, distinct differences are apparent between metastatic and nonmetastatic tumors in macrophage distribution into the elutriated fractions. The distribution of the tumor-associated macrophages was shifted toward the later fractions in the metastatic tumors (lines 66 and 410.4), with approximately 40% more macrophages in fractions 3 and 4 than in those fractions from the nonmetastatic tumors (lines 67 and 168). The levels of three ectoenzymes, leucine aminopeptidase (LAP), alkaline phosphodiesterase I (APD), and 5' nucleotidase (5'N) were determined for macrophages from the elutriated fractions as well as for the total tumor digest. No significant differences were observed in absolute levels of either LAP or APD between most of the fractions from the different tumor lines. Differences were seen between the fractions in levels of 5'N among the lines and in ADP levels between lines 66 and 168 from the total tumor digest. Striking differences in ectoenzyme levels were apparent when the activity was normalized to macrophage surface area: macrophages from line 66 tumors were 3- to 17-fold higher in their LAP concentrations than were macrophages from either 67 or 168 tumors. Each tumor line had a unique and reproducible pattern of macrophage-associated prostaglandin E (PGE) synthesis. The three nonmetastatic tumor lines showed peak PGE levels in fraction three with lower levels in fraction 2, whereas the highly metastatic tumor yielded more active macrophages in fraction 2 vs fraction 3. Changes in PGE levels were associated with differing ectoenzyme levels. Macrophages in fraction 3 from metastatic tumors were enriched for populations with high LAP activity and low PGE levels. Conversely, macrophages from nonmetastatic tumors exhibited lower LAP activity in fraction 3 vs 2 and increasing PGE levels. Thus, differences between metastatic and nonmetastatic mammary tumors were seen in 1) distribution of macrophages in the elutriation fractions, 2) size of infiltrating macrophages, 3) macrophage ectoenzyme concentrations, and 4) macrophage-associated PGE levels.

Animals↗
PubMed2002

A role for endogenous IL-12 in tumor immunity: IL-12 is required for the acquisition of tumor-migratory capacity by T cells and the development of T cell-accepting capacity in tumor masses.

Interleukin (IL)-12 plays a central role in the initiation and regulation of T cell-mediated immune responses. The present study investigated how IL-12, endogenously produced during tumor vaccination, functions for anti-tumor immune responses. Mice were given anti-IL-12 monoclonal antibody during immunization with attenuated syngeneic tumor cells. Splenic T cells from anti-IL-12-treated immunized mice exhibited comparable levels of tumor-neutralizing activity with those from tumor-immunized mice without anti-IL-12 treatment. When these two groups of mice were directly challenged with viable tumor cells, tumor rejection was induced only in anti-IL-12-untreated mice. T cell infiltration was observed at the site of tumor challenge in these mice, whereas such a T cell infiltration did not occur in anti-IL-12-treated mice. The tumor-migratory capacity was directly assessed by transferring spleen cells from tumor-immunized mice into syngeneic, tumor-bearing recipient mice and by quantitating donor cells migrating into recipients' tumor masses. T cells from anti-IL-12-treated tumor-immunized mice were found to exhibit a markedly reduced tumor-migratory capacity when compared with that of anti-IL-12-untreated mice. Moreover, the migration of T cells from anti-IL-12-untreated mice to tumor masses prepared in anti-IL-12-treated mice was severely reduced. These results indicate that endogenously produced IL-12 has dual roles in anti-tumor-immune resistance: One is to confer T cells with a tumor-migratory capacity, and the other is to allow tumor masses to develop the capacity to accept tumor-migrating T cells.

Animals↗
PubMed1993

Rat adenocarcinoma 13762 expresses tumor rejection antigens but tumor-bearing animals exhibit tumor-specific immunosuppression.

Rat adenocarcinoma 13762 was adapted to continuous growth in culture and used in a variety of experiments to investigate the immune response to inoculation of animals with replication-defective tumor cells. The results demonstrate that 13762 cells express tumor-specific tumor rejection antigens that elicit protective immunity to tumorigenic challenge. By several criteria there is no apparent humoral component of the anti-tumor immunity; however, anti-tumor immunity is characterized by nylon-wool nonadherent spleen T cells. Anti-tumor T cells demonstrate tumoricidal activity in local adoptive transfer assays and are not found in spleens of naive animals or animals immunized against either nontumorigenic Rat 1 cells or a syngeneic fibrosarcoma. Despite the expression of tumor rejection antigens 13762 tumor, and the demonstrable ability of injection of irradiated tumor to induce anti-tumor immunity, tumors elicited in unimmunized syngeneic animals grow progressively. The reasons for growth of antigenic tumor are unknown but are shown not to be due to defective antigen expression in 13762 tumor since, in addition to being able to elicit T cell immune response in immunized animals, 13762 tumor expresses MHC Class I molecules and can be a target for allogeneic T cell recognition in vitro. These data suggest that in tumor-bearing animals an effective anti-tumor immune response is either not initiated or down-regulated. Since animals bearing 13762 tumors can be immunized against an unrelated syngeneic sarcoma, can produce humoral responses to several protein antigens, and can produce delayed type hypersensitivity response against dinitrofluorobenzene, the immune response to 13762-induced tumors appears specifically suppressed. In support of this contention, 13762 cells express high levels of transforming growth factor beta 1 in vitro which is postulated to impact upon the nascent anti-tumor immune response.

Adenocarcinoma↗
PubMed2006

Relationships among tumor burden, tumor size, and the changing concentrations of fibrin degradation products and fibrinolytic factors in the pleural effusions of rabbits with VX2 lung tumors.

The VX2 tumor is derived from a papilloma virus-induced rabbit epithelial cell line. If VX2 tumor cells (trapped in a plasma clot) are introduced intravenously into NZW rabbits, the cells lodge in the lung capillary bed and produce tumors. Independently of the tumor burden (ie, the total tumor weight per rabbit), approximately 15% of rabbits with VX2 lung tumors accumulate an effusion in the interpleural space and this pleural effusion contains products of hemostasis. We hypothesized that these products were of intra-tumoral origin and that they changed in concentration as tumor burden increased. Interrelationships among lung-, tumor-weights, and pleural effusion volumes, and the concentrations of fibrinolytic factors, their catabolic products, and other proteins of pleural effusions were measured in rabbits with a wide range of tumor burdens. Positive correlations between tumor burden and total lung weight and between pleural effusion volume and net lung weight suggested that interstitial fluid from the stroma of tumors passed directly into the extravascular space of the lung(s) and into the interpleural space(s). Analyses of pleural effusions indicated that plasminogen-, alpha(2)-antiplasmin-, and plasminogen activator inhibitor-1-related proteins, urokinase-like- and tissue-plasminogen activator activities, and vascular endothelial growth factor increased in concentration up to a tumor burden of approximately 20-25 g. Plasmin activity and intact fibrinogen were absent. The concentration of fibrin(ogen) degradation products did not change significantly up to a tumor burden of approximately 25 g but increased substantially as tumor burdens exceeded 25 g. In conclusion, interstitial fluid from tumors enters the extravascular space of the host and may accumulate with fluid from non-tumor sources as a pleural effusion. The concentrations of fibrinolytic factors and their products in pleural effusions reflect the tumor burden of the rabbit. Conceivably, the components of a malignant effusion contain much information about the extent of tumor growth.

Animals↗
PubMed1990

Tumor infiltrating leukocytes (tils) during progressive tumor growth and BCG-mediated tumor regression.

Tumor regression was induced by intralesional injection with BCG, 7 days after inoculation of line 10 hepatocellular carcinoma cells into strain 2 guinea pigs. Tumor-infiltrating leukocytes (TILS) were characterized immunohistochemically with 11 monoclonal antibodies (MoAbs) during the induction phase of line 10-immunity, and during immune-mediated regression of the tumor, at days 12 and 28 after tumor cell inoculation, respectively. At day 5 after BCG-injection (day 12 after tumor cell inoculation), there were no major differences between the TIL subpopulations of the BCG-treated and untreated tumors. The TILS were mainly T-cells, as identified by MoAbs against Pan T-cells (CT5), T-cytotoxic/suppressor cells (CT6) and T-helper/inducer cells (H155). A limited number of macrophages was also present. However, at day 21 after BCG-treatment (28 days after tumor cell inoculation), the fibrous stroma was increased dramatically in most of the BCG-treated tumors, and as a result, the tumor cell islets were smaller than in control tumors. In the BCG treated tumors, the numbers of T-cells and macrophages were increased. In growing and regressing tumors, MHC class I and II antigens were strongly expressed in TILS and in the tumor stroma. Line 10 tumor cells prior to inoculation expressed no MHC class I or II antigens. In the centers of the tumor islets at days 12 and 28, expression of these antigens was not found. However, MHC class I and II antigens were expressed on tumor cells at sites where they lay close to the fibrous stroma or TILS. This observation was made in progressively growing tumors and was most apparent in BCG-treated tumors.

Animals↗
PubMedDate not supplied

Treatment of established tumor is associated with ICAM-1 upregulation and reversed by CD8 depletion in a tumor necrosis factor-alpha gene transfected mouse mammary tumor.

INTRODUCTION: We have performed TNF-alpha gene transfection in a mouse mammary cancer line and found significant antitumor effects. We hypothesize that the antitumor effects observed in this model are mediated by ICAM-1 and by the recruitment of CD4+ and CD8+ T cells. In vivo (Balb/c mice) tumor growth inhibition, treatment of established tumor and the effects of ICAM-1 and CD4+ and CD8+ T cells were evaluated. METHODS AND RESULTS: Gene transfection with highly efficient vectors resulted in secretion of large amounts of TNF-alpha (ELISA). In vivo antitumor effects were tested. The number of cells required to generate palpable tumor 7-10 days after subcutaneous injection was determined (1 x 10(6)). The same number of transfected cells were injected subcutaneously and compared to nontransfected controls. Tumors were measured blindly and size was analyzed on day 30 by the Wilcoxon rank sum test. Mean tumor size after injection of transfected cells is compared to that of controls. Control tumors reached the maximum allowable size by day 30 (4 cm(2)). On day 30 EMT6-TNF-alpha tumors were 0.48 cm(2) (p < 0.05). The effect of repeat injection (challenge was also tested. Animals were injected with transfected cells or wild-type control on day -6 and challenged with the same number of wild-type tumor cells on day 0. Significant immune protection against subsequent challenge was seen after first time injection with EMT6-TNF-alpha but not after first time EMT6 wild-type injection (1.62 vs. 4 cm(2)). Treatment of 6-day-old tumor was also evaluated. On day 30, mean tumor size in animals treated with EMT6-TNF-alpha was 0.9 cm(2) compared to 4 cm(2) for controls. In all experiments, CD8+ T cell depletion and CD4+ T cell depletion caused a reversal of TNF-alpha-induced inhibitory effects. In addition, in vivo antibody blocking of ICAM-1 in tumor growth experiments reversed antitumor effects (control 4 cm(2), TNF-alpha 0.2 cm(2) and ICAM-1 blocking 3.14 cm(2)). Using flow cytometry, MHC class I and II and ICAM-1 adhesion molecule expression of transfected tumor was tested. ICAM-I expression was significantly upregulated. MHC class II antigen expression was also increased. TNF-alpha-transfected human breast cancer was also evaluated. Three cell lines and fresh tumor were transfected to express TNF-alpha. In vitro analysis revealed ICAM-1 upregulation following transfection. Histologic analysis and immunohistochemical staining revealed TNF-alpha and ICAM-1 in transfected tumors and not in wild-type tumors. CONCLUSION: Highly significant in vivo tumor growth inhibition and immune protection after injection with TNF-alpha-transfected tumors appears to be mediated predominantly by CD8+ T cells and ICAM-1 upregulation. These findings suggest that TNF-alpha increases recruitment and adhesion of effector T cells.

Animals↗
PubMed1975

The incidence of yolk sac tumor (endodermal sinus tumor) elements in germ cell tumors of the testis in adults.

The incidence of yolk sac tumor (endodermal sinus tumor) elements was studied in 147 germ cell neoplasms of the testis in adults observed over a 4 1/2-year period. Excluding 79 cases of pure seminoma, yolk sac tumor elements were found in 26 (38%) of 68 tumors; in 8 tumors the yolk sac tumor was the predominant element. Yolk sac tumor elements were found admixed with all other germ cell tumor elements. Tumors composed entirely of yolk sac tumor were not encountered. Fifteen (57%) of the 26 patients with tumors containing yolk sac tumor elements have died of their disease during the period under study, compared with 13 (31%) of the remaining 42 patients, suggesting that the prognosis of adults with testicular tumors containing yolk sac tumor elements is unfavorable. This is in contrast to the relatively good prognosis of infants and young children with testicular yolk sac tumor, and similar to the prognosis of female patients with ovarian yolk sac tumor. The results of the present study give further support to the view that yolk sac tumor (endodermal sinus tumor) is not adistinctive neoplasm of the infant's testis, but a germ cell neoplasm differentiating in the direction of yolk sac or vitelline structures, and occurring in the testis, ovary and extragonadal sites in common with other germ cell neoplasms.

Adolescent↗
PubMed2002

Epithelioid endometrial and endometrioid stromal tumors: a report of four cases emphasizing their distinction from epithelioid smooth muscle tumors and other oxyphilic uterine and extrauterine tumors.

Three endometrial and one extrauterine endometrioid stromal tumors (three sarcomas and one stromal nodule) with a prominent component of epithelioid cells with abundant eosinophilic cytoplasm are described. The patients were 39, 48, 56 and 86 years of age. The endometrial sarcomas were described grossly as an ill-defined tan nodule and "ragged and papillary," respectively, and had the typical infiltrative pattern of low-grade endometrial stromal sarcoma. The stromal nodule was a 13-cm, well circumscribed, yellow, fleshy mass. The extrauterine tumor was probably primary in the sigmoid colon. Oval to polygonal epithelioid cells with abundant eosinophilic cytoplasm accounted for 50% to 90% of the tumor cells. The cytoplasm was granular in one case. None of the tumors contained cells with a rhabdoid appearance. Nuclear and other features did not differ from those of usual endometrial-endometrioid stromal tumors except in one case in which there was greater nuclear pleomorphism. There was strong diffuse cytoplasmic immunoreactivity of all four tumors for vimentin and for CD10 in three of three tumors tested, as well as extensive and moderate reactivity for NK1/C3 and focal weak reactivity for CD68 in two of three tumors tested. Muscle actin positivity was very focal to extensive and weak to strong in all three tumors tested, mainly in the epithelioid areas; alpha-smooth muscle actin was focally to extensively positive in the epithelioid areas of two of three tumors tested; and focal strong desmin positivity (interpreted as indicating smooth muscle metaplasia) was found in the epithelioid areas of one of four tumors. A vaginal recurrence in one case had similar cytologic features to the primary tumor but when examined initially in the absence of adequate history posed diagnostic difficulty, as did evaluation of the uterine tumor in two other cases and the extrauterine tumor in the final case. The differential in these cases is primarily with an epithelioid smooth muscle tumor when they are uterine primaries. The typical infiltration facilitates this distinction in the cases of endometrial stromal sarcomas, but this feature is usually only evident in hysterectomy specimens. In limited samples such as biopsy or curettage specimens, and in some cases of recurrent tumor, awareness that endometrial-endometrioid stromal tumors can have epithelioid cells is crucial in the formulation of the differential diagnosis. Diverse oxyphilic tumors, including deciduoid malignant mesothelioma, can potentially be in the differential diagnosis with extrauterine (endometrioid) stromal sarcomas with epithelioid cells. Immunohistochemical evaluation may potentially provide major aid in diagnosis.

Adult↗
PubMedDate not supplied

Effects of social housing condition on chemotherapeutic efficacy in a Shionogi carcinoma (SC115) mouse tumor model: influences of temporal factors, tumor size, and tumor growth rate.

OBJECTIVE: The objective of this study was to investigate 1) whether social housing condition, tumor size, and tumor growth rate alter responses to chemotherapy and 2) whether the timing of tumor cell injection or chemotherapy initiation (relative to housing condition formation) influences tumor growth rate or the efficacy of chemotherapy. METHODS: Mice were reared individually (I) or in groups (G). In experiment 1, mice were rehoused (IG or GI) or left in group housing (GG) immediately after tumor cell injection. In experiment 2, housing conditions (II, IG, GG, or GI) were formed when tumors weighed 1 g. Chemotherapy (adriamycin 4 mg/kg and cyclophosphamide 61.5 mg/kg IP) and exposure to acute novelty stress (15 min/d, 5 d/wk) were initiated 1 day after housing condition formation. RESULTS: If chemotherapy was initiated when the tumor burden was undetectable (experiment 1), housing condition did not alter tumor response to chemotherapy, although IG mice lost the most weight and overall had the lowest probability of survival. If chemotherapy was initiated when tumors weighed 1 g (experiment 2), both tumor and host responses to chemotherapy were poorest for IG mice. Timing of tumor cell injection relative to housing condition formation also differentially influenced the rate of tumor growth in mice treated with the drug vehicle; in experiment 1, tumor growth rate was faster in GI and GG mice than in IG mice, whereas in experiment 2, the rate of tumor growth was faster in II mice than in GG and IG mice. CONCLUSIONS: Altering the temporal relationships among social housing condition formation, tumor cell injection, and chemotherapy initiation differentially influences the rate of tumor growth and the efficacy of chemotherapy. Effects of housing condition are independent of tumor growth rate at chemotherapy initiation and, in terms of host responses, independent of tumor burden.

Animals↗
PubMed1979

Assessment of host immune status during progressive growth and after excision of DNA virus (simian virus 40) tumors in hamsters: comparison of tumor-specific and tumor-unrelated parameters of immune responsiveness.

The kinetics of cell-mediated immunity to simian virus 40 (SV40) tumor-specific transplantation antigen (TSTA) were compared to the kinetics of tumor-unrelated parameters of immune responsiveness in the assessment of the immune statuses of inbred MHA/SsLAK hamsters during the course of progressive syngeneic SV40 tumor growth and after tumor excision. With the use of the tumor cell neutralization test in vivo and the macrophage migration inhibition assay in vitro, specific cellular immunity to SV40 TSTA was detected by 4 days after tumor cell inoculation, when the tumor was small. This tumor-specific immune response was no longer detected at 7 days after tumor cell inoculation, when the tumor had reached a mean diameter of 12.5 mm, but it returned by 14 days after surgical excision of the tumor. The patterns of host responsiveness to mitogens in spleen cells derived from tumor-bearing animals or from tumor-excised animals generally showed little or no correlation with the kinetics of tumor-specific cellular immunity. The kinetics of the humoral immune response to murine erythrocytes, as determined by hemagglutination assays, correlated much more closely with the kinetics of tumor-specific immunity than did the responses to mitogens. IgG antibody (T-dependent) responses were more affected by progressive tumor growth than were IgM antibody (T-independent) responses. The data suggest that results of tests with the use of tumor-unrelated parameters of immune responsiveness for the assessment of the immune status of cancer patients should be interpreted with caution.

Animals↗
PubMed2005

Transient exposure of mammary tumors to PD184352 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth.

Previous studies from our group have demonstrated in vitro that UCN-01 (7-hydroxystaurosporine) and inhibitors of MEK1/2 interact to cause tumor cell death in a wide variety of malignant, but not in nontransformed, cell types. The present studies determined whether UCN-01 and MEK1/2 inhibitors interacted to cause tumor cell death in vivo. In vitro colony formation studies demonstrated that UCN-01 and the MEK1/2 inhibitor PD184352 interacted to synergistically kill human mammary carcinoma cells (MDA-MB-231, MCF7) with similar combination index values. Athymic mice were implanted in the rear flank with either MDA-MB-231 or MCF7 cells and tumors permitted to form to a volume of approximately 100 mm3 prior to a two day exposure of either Vehicle, PD184352 (25 mg/kg), UCN-01 (0.1-0.2 mg/kg) or the drug combination. Tumor volume was measured every other day and tumor growth determined over the following approximately 30 days. Transient exposure of MDA-MB-231 tumors or MCF7 tumors to either PD184352 or UCN-01 did not significantly alter tumor growth rate or the mean tumor volume in vivo approximately 15-30 days after drug administration. In contrast, combined treatment with PD184352 and UCN-01 significantly reduced MDA-MB-231, and largely abolished MCF7 tumor growth. Tumor control values for both cell lines were 0.36. Tumor cells isolated approximately 30 days after combined drug exposure exhibited a significantly greater reduction in plating efficiency using ex vivo colony formation assays than tumor cells that were exposed to either drug individually. Reduced tumor growth correlated with profound tumor cell death within five days of combined drug exposure, which was also evident approximately 30 days after exposure. In addition, tumor cell death correlated with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31. Collectively, these findings argue that UCN-01 and MEK1/2 inhibitors have the potential to suppress mammary tumor growth in vivo which is independent of p53 status, estrogen dependency, caspase 3 levels or oncogenic K-RAS expression.

Apoptosis↗
PubMed2006

Immunohistochemical analysis of INI1 protein in malignant pediatric CNS tumors: Lack of INI1 in atypical teratoid/rhabdoid tumors and in a fraction of primitive neuroectodermal tumors without rhabdoid phenotype.

Immunohistochemical lack of nuclear INI1 protein expression has been recently described as characteristic finding in atypical teratoid/rhabdoid tumors (AT/RTs), and has been suggested as useful marker to distinguish AT/RTs from other malignant pediatric central nervous system (CNS) tumors. In this study, we examined a large series of malignant pediatric CNS tumors to determine the immunohistochemical expression of INI1 protein in different malignant pediatric tumor entities. Archival paraffin-embedded biopsy specimens of 289 malignant pediatric CNS tumors including medulloblastomas, supratentorial primitive neuroectodermal tumors, glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, choroid plexus carcinomas, germ cell tumors, and AT/RTs were analyzed immunohistochemically for expression of nuclear INI1 protein. Positive INI1 staining was observed in 263 tumors. Lack of INI1 protein was detectable in 26 tumors. Seventeen of the 26 tumors showed morphologically characteristic features of AT/RTs, whereas 9 embryonal tumors did not display rhabdoid features. Tumors without rhabdoid phenotype but lack of INI1 showed an aggressive clinical course and poor response to conventional treatment regimens. In summary, immunohistochemical expression of INI1 protein is lacking in tumors displaying characteristic morphologic features of AT/RT. Furthermore, a certain number of embryonal tumors without rhabdoid features but lack of INI1 protein and aggressive biologic behavior can be detected. We conclude that INI1 protein analysis should be routinely performed in all malignant pediatric embryonal CNS tumors to detect cases with lack of INI1 protein, because patients with these tumors are likely to benefit from intensified treatment.

Biomarkers, Tumor↗
PubMed1976

Detection of anti-tumor antibody in virally induced tumors and its relationship to tumor growth.

The humoral antibody response to virally induced tumors insyngeneic hosts has been studied. The tumors include an SV40 tumor SVT2, the Friend virus-induced leukemias FBL-3 and FLC; and Moloney sarcoma virus-induced tumors. It was found that antitumor antibodies could be detected by the isotopic antiglobulin technique in these tumor systems at a relatively early stage of tumor growth. The kinetics of the antibody response in relation to the status of tumor growth varied between different tumors. In geneumor growth than in the regressors of tumor-free hosts. Reinoculation of tumor cells or recurrence of tumor growth produced elevation of antibody levels (secondary response). The specificity of the antibody reactions also varied in different tumor systems: some antibodies were truly tumor-specific and thus might produce a biological effect on in vivo tumor immunity, whereas others were not. These studies indicated that a sensitive antibody assay could be used for early detection of tumor growth. However, its usefulness in evaluation of the status of tumor growth should be carefully studied in each tumor system.

Animals↗
PubMed2003

Genetic analysis of three-dimensional shape of mouse lung tumors reveals eight lung tumor shape-determining (Ltsd) loci that are associated with tumor heterogeneity and symmetry.

Most lung tumor linkage studies focus on identifying loci that confer susceptibility or resistance irrespective of the tumor types developed. However, different mouse strains develop different types of lung tumors. A major obstacle for genetic studies of these differences is the lack of reproducible, quantitative, and uniform assessment of tumor type. We have previously described a new variable (Rratio) that assesses the three-dimensional shape of lung tumors in a quantifiable way and showed that nonspherical tumors are correlated with tumor heterogeneity and with a tendency to asymmetrical growth (N. Tripodis and P. Demant, Exp. Lung Res., 27: 521-531, 2001). In the present study, we use the Rratio variable to search for quantitative trait loci affecting tumor phenotype. We tested the F(2) cross between the susceptible strain O20 and the recombinant congenic strain OcB-9. Both develop mixed alveolar and papillary lung tumors, and the OcB9 tumors are, on average, more elongated than the O20 ones. We mapped eight new lung tumor shape-determining loci (Ltsd1-8) involved in mutual interactions. Two of these loci, Ltsd1 and Ltsd3, seem to play a major role in tumor shape formation. The Ltsd4 locus was confirmed in a second F(2) cross between strain O20 and the recombinant congenic strain OcB-6. Genotype-phenotype associations show that nonspherical tumors are correlated with tumor heterogeneity and nonsymmetrical (focal) development of structures. Most of the new Ltsd loci map in regions where susceptibility to lung cancer (Sluc) loci have been previously mapped, raising the question of whether they are identical or closely linked loci. Based on models of tumor growth indicating that supply of nutrients and the ability to create a capillary network may be shape-determining factors (G. P. Pescarmona et al., Med. Hypoth., 53: 497-503, 1999), we suggest as likely candidates for the Ltsd loci genes involved in angiogenesis, vascularization, and capillary patterning. This is the first set of loci that affects qualitative aspects of lung tumors and may provide biologically and clinically interesting indicators of lung tumor progression.

Animals↗
PubMed2006

Infiltration of tumor-reactive transforming growth factor-beta insensitive CD8+ T cells into the tumor parenchyma is associated with apoptosis and rejection of tumor cells.

BACKGROUND: TGF-beta is a potent immunosuppressant. High levels of TGF-beta produced by cancer cells have a negative inhibition effect on surrounding host immune cells and leads to evasion of the host immune surveillance and tumor progression. In the present study, we report a distinct ability of tumor reactive, TGF-beta-insensitive CD8+ T cells to infiltrate into established tumors, secrete relevant cytokines, and induce apoptosis of tumor cells. METHODS: CD8+ T cells were isolated from the spleens of C57BL/6 mice, which were primed with irradiated mouse prostate cancer cells, the TRAMP-C2 cells. After ex vivo expansion, these tumor reactive CD8+ cells were rendered TGF-beta-insensitive by infection with a retroviral (MSCV)-mediated dominant negative TGF-beta type II receptor (TbetaRIIDN). Control CD8+ cells consist of those transfected with the GFP-only empty vector and naïve CD8+ T cells. Recipient mice were challenged with a single injection of TRAMP-C2 cells 21 days before adoptive transfer of CD8+ T cells was performed. Forty days after the adoptive transfer, all animals were sacrificed. The presence of pulmonary metastases was evaluated pathologically. Serial slides of malignant tissues were used for immunofluorescent staining for different kinds of immune cell infiltration, cytokines, and apoptosis analysis. RESULTS: Pulmonary metastases were either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells (3 out of 12) when compared to GFP controls (9 out of 12), and naïve CD8+ T cells (12 out of 12). Results of immunofluorescent studies demonstrated that only tumor-reactive TGF-beta-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis when compared to CD4+ T cells, NK cells, and B cells. A large amount of cytokines such as perforin, nitric oxide, IFN-gamma, IL-2, TNF-alpha were secreted in tumor tissue treated with tumor-reactive TGF-beta-insensitive CD8+ T cells. No immune cells infiltration and cytokine secretion were detected in tumor tissues treated with naïve T cells and GFP controls. CONCLUSIONS: Our results demonstrate the mechanism of anti-tumor effect of tumor-reactive TGF-beta-insensitive CD8+ T cells that adoptive transfer of these CD8+ T cells resulted in infiltration of these immune cells into the tumor parenchyma, secretion of relevant cytokines, and induction of apoptosis in tumor cells. These results support the concept that tumor-reactive TGF-beta-insensitive CD8+ T cells may prove beneficial in the treatment of advanced cancer patients.

Animals↗
PubMedDate not supplied

Human inflammatory cells within the tumor microenvironment of lung tumor xenografts mediate tumor growth suppression in situ that depends on and is augmented by interleukin-12.

The human tumor microenvironment includes a mixture of tumor cells, inflammatory cells, fibroblasts, and endothelial cells, all of which are tethered to an extracellular matrix. It has been difficult to study the dynamic interactions of these cells in human tumors in situ for obvious ethical and logistical considerations that prohibit experimental manipulations of tumors while still in patients. Fresh tissue from human lung tumor biopsy implanted into SCID mice was shown to remain viable, and the histologic appearance of the tumor microenvironment was maintained in the tumor xenografts for at least 3 months. In this study, the authors established that the inflammatory cells within human tumor xenografts can suppress tumor growth, and that this suppression is a result, in part, of endogenously produced interleukin-12 (IL-12) because IL-12 neutralizing antibodies enhance the growth of the tumor xenografts. The tumor-inhibitory activity of the inflammatory leukocytes is also enhanced by the local and sustained release of human recombinant IL-12 into the tumor microenvironment from cytokine-loaded biodegradable microspheres. Neither the anti-IL-12 neutralizing antibody nor the delivery of exogenous IL-12 from microspheres had any effect on tumor xenografts in the absence of the inflammatory leukocytes. In conclusion, the inflammatory cells within the tumor microenvironment of human lung tumor xenografts are functional and can suppress tumor growth, and the dynamic effects of the inflammatory cells can be modulated by exogenous cytokines.

Adjuvants, Immunologic↗